Post on 10-Jun-2018
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The Hippo signal transduction network for exercise physiologists 1
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Brendan M. Gabriel1,7,8, D Lee Hamilton2, Annie M Tremblay3,4,5, Henning Wackerhage1,6*3
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1. School of Medicine, Dentistry and Nutrition, University of Aberdeen, Scotland, UK 5 2. School of Sport, University of Stirling, Scotland, UK 6 3. Stem Cell Program, Children's Hospital, Boston, MA, USA 7 4. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 8
USA 9 5. Harvard Stem Cell Institute, Cambridge, MA, USA. 10 6. Faculty of Sport and Health Science, Technical University Munich, Germany 11 7. The Novo Nordisk Foundation Center for Basic Metabolic Research, Section for 12
Integrative Physiology, University of Copenhagen, Copenhagen, Denmark 13 8. Integrative physiology, Department of Physiology and Pharmacology, Karolinska 14
Institutet, Stockholm, Sweden 15 16
BMG, DLH, AMT and HW all contributed to the conception and writing of this review. 17
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Running head: The Hippo pathway for exercise physiologists 19
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*Corresponding author: 21
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Prof Henning Wackerhage 23 24 Faculty for Sport and Health Sciences 25 Technical University Munich 26 Uptown München-Campus D 27 Georg-Brauchle-Ring 60/62 28 D-80992 München 29 Germany 30
Email: henning.wackerhage@tum.de 31
Tel: +49.89.289.24601 32 Fax: +49.89.289.24605 33
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Articles in PresS. J Appl Physiol (March 3, 2016). doi:10.1152/japplphysiol.01076.2015
Copyright © 2016 by the American Physiological Society.
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Abstract 35
The ubiquitous transcriptional co-activators Yap (gene symbol Yap1) and Taz (gene symbol 36
Wwtr1) regulate gene expression mainly by co-activating the Tead transcription factors. 37
Being at the centre of the Hippo signalling network, Yap and Taz are regulated by the Hippo 38
kinase cassette and additionally by a plethora of often exercise-associated signals and 39
signalling modules. These include mechanotransduction, the AKT-mTORC1 network, the 40
SMAD transcription factors, hypoxia, glucose homeostasis, AMPK, adrenaline/epinephrine 41
and angiotensin II through G protein-coupled receptors, and interleukin 6 (Il-6). 42
Consequently, exercise should alter Hippo signalling in several organs to mediate at least 43
some aspects of the organ-specific adaptations to exercise. Indeed, Tead1 overexpression 44
in muscle fibres has been shown to promote a fast-to-slow fibre type switch, whereas Yap in 45
muscle fibres and cardiomyocytes promotes skeletal muscle hypertrophy and cardiomyocyte 46
adaptations, respectively. Finally, genome wide-association studies in humans have linked 47
the Hippo pathway members LATS2, TEAD1, YAP1, VGLL2, VGLL3 and VGLL4 to body 48
height, which is a key factor in sports. 49
50
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Keywords 52
Exercise, Hippo, Hypertrophy, Skeletal Muscle, Yap 53
54
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Introduction 55
Especially during the last decade, key discoveries have led to the characterisation of the 56
mammalian Hippo signal transduction pathway or network (51, 141, 159). The Hippo signal 57
transduction network is relevant for exercise physiologists because many exercise-58
associated signals and signalling molecules affect Hippo signalling. Additionally, Hippo 59
effectors regulate several exercise-related genes and adaptations. Starting with Booth in the 60
mid-1990s (19), exercise physiologists have sporadically studied the Hippo pathway 61
members in an exercise context. However, to date only few studies on Hippo in an exercise 62
context have been published. In this review, we will first introduce the Hippo pathway to 63
exercise physiologists. We will then discuss evidence showing that exercise-associated 64
signals and signalling modules cross-talk to the key Hippo effectors YAP and TAZ. Next, we 65
will review studies that implicate Hippo signalling in the regulation of exercise adaptations. 66
Finally, we will discuss the emerging genetic link between Hippo and body height, a key 67
variable linked to performance in several sports. 68
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Hippo signal transduction pathway and network 70
The discovery of the Hippo pathway is based on two strands of research. First, since the 71
early 20th century, researchers have used the fruit fly (Drosophila melanogaster) to identify 72
genes whose knock out results in cancer-like overgrowth (40). Since 1995, this line of 73
research has led to the discovery of the several growth-inhibiting genes (68, 156) that 74
together form the core Hippo pathway (56). In the fly, the mutation of one kinase resulted in 75
an overgrown head that reminded the researchers of the Hippopotamus’ skin. Consequently, 76
this kinase was named hippo by the Halder group. (134). Subsequently “Hippo” was adopted 77
as the name for the pathway in both the fly and mammals. The Hippo pathway is highly 78
conserved evolutionarily (60). In mammals (see Figure 1 for a schematic of the mammalian 79
Hippo pathway), two homologues of the fly hippo gene exist, namely the upstream kinases 80
Mst1 (Stk4) and Mst2 (Stk3). With the help of scaffolding proteins, Mst1 and Mst2 activate 81
the downstream kinases Lats1 and Lats2. Recently, Map4k4/6/7 isoforms were identified as 82
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alternative kinases capable of phosphorylating Lats1/2 (82, 97, 165). Phosphorylated Lats1 83
and Lats2 then inhibit the transcriptional co-factors Yap and Taz by phosphorylating multiple 84
serine residues (86, 162). 85
86
The second strand of research started with the identification of CATTCC DNA motifs, termed 87
muscle CAT (MCAT) (90) or GTIIC (24) motifs. Such CATTCC DNA motifs and their reverse 88
strand GGAATG complement form a DNA binding site for the Tead (TEA domain) 89
transcription factors (named Transcription enhancer factors or Tefs in earlier papers) (6, 24). 90
Teads repress their target genes, especially when bound by their co-repressor Vgll4 (66, 91
76). Teads only become activated when bound by the transcriptional co-factor Yap (Yes1-92
associated protein; gene symbol Yap1), which was discovered by Sudol (122, 123, 138). In 93
contrast to the fly, mammals possess a Yap paralogue termed Taz (Transcriptional 94
coactivator with PDZ-binding motif (70)). 95
96
The two origins of Hippo research were only merged when the Pan group demonstrated that 97
the Hippo kinase cascade inhibited Yorkie, the fly homologue of Yap and Taz (63). Hippo 98
research then developed exponentially especially after the Pan group (29) and Camargo 99
from the Jaenisch group (18) both found that the expression of a constitutively active YAP1 100
S127A in mouse livers resulted in a 4-fold liver size increase. These landmark findings 101
confirmed that Yap also functions as a highly potent organ size regulator in mammals. 102
103
However, the Hippo kinase (i.e. the Mst1/2-Lats1/2 kinase cascade) is only one of many 104
signalling modules that regulate the activity of Yap and Taz. For this reason, it seems most 105
appropriate to refer to the wider signalling system as the Hippo signal transduction network. 106
Importantly, numerous exercise-related signals also cross-talk to Yap and Taz, as illustrated 107
in Figure 1 and discussed in the next section. 108
109
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Figure 1. Schematic representation of the Hippo signal transduction network and its links to
exercise-associated signals and signalling modules. A, MST1, MST2, LATS1 and LATS2
form the core kinase cassette of the Hippo pathway. SAV1 and MOB1 act as scaffolding
proteins. The MAP4K 4, 6 and 7 kinase isoforms can independently regulate LATS1/2 (82,
97, 165). Active LATS1 and LATS2 inhibits YAP and TAZ through the phosphorylation of
multiple HXRXXS motifs (where “S” indicates the phosphorylated serine) (162).
Phosphorylation of YAP on serine 127 generates a binding site for 14-3-3 proteins, which
sequester YAP and TAZ in the cytoplasm. Phosphorylation of serine 381 results in the
ubiquitation and degradation of YAP (162). Similar regulatory events also affect TAZ. B, The
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classical model stipulates that active unphosphorylated YAP and TAZ are nuclear and co-
activate the TEAD transcription factors, whereas VGLL4 acts as a repressor. YAP/TAZ-
TEAD complexes bind the CATTCC/GGAATG (MCAT or GTIIC) motifs found especially in
enhancers that loop to the promoters of genes even though they are located several base
pairs away from the promoter itself (39). C, Resistance (strength) exercise and muscle
growth-associated signals that are linked to YAP/TAZ (see text for more detail). D,
Endurance exercise-associated signals that are linked to YAP/TAZ (see text for more detail).
110
Cross-talk between exercise-related signalling molecules and Hippo 111
Mechanotransduction 112
Mechanical loading, in the form of resistance exercise or synergist ablation, stimulates 113
skeletal muscle growth (42). However, the molecular mechanosensor that triggers growth 114
processes in response to mechanical loading has long remained elusive. Additionally, the 115
stiffness of the cellular environment or niche is an additional mechanical signal that 116
influences for example the differentiation of mesenchymal stem cells into muscle and other 117
cell types (34, 35). Moreover, mechanical cues also influence the fate of resident stem cells 118
in skeletal muscle, named satellite cells (41). To identify signalling molecules that regulate 119
gene expression in response to the mechanical signal triggered by substrate stiffness, the 120
Piccolo group cultured mammary epithelial cells (MEC) on soft and stiff substrates. They 121
found that Hippo-related genes showed the most important changes between the two 122
conditions in terms of expression levels (31). Subsequent experiments confirmed that stiffer 123
substrates led to increased Yap/Taz activity in a cytoskeleton-dependent manner (31). Later, 124
it was shown that increased cell-cell contact reduces the mechanical loading of cells, which 125
explained the previously observed (163) deactivation of Yap and Taz in response to cell-cell 126
contact at high cell density (8). Whilst this is intriguing and relevant for processes such as 127
myoblast differentiation, it is unclear whether mechanical changes of the extracellular matrix 128
during exercise regulate transcriptional responses through Yap and Taz in muscle fibres or 129
satellite cells. 130
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131
In skeletal muscle, the Höhfeld group has identified a specific Hippo and autophagy-132
regulating mechanosensor complex located at the Z disc. In this complex, the protein Bag3 133
senses mechanical unfolding of the actin-crosslinking protein filamin (135). Importantly, 134
Bag3 contains a WW domain, a rare protein domain frequently found in Hippo members 135
(WW indicates two tryptophan residues; reviewed by (124)). The location of Bag3 in the Z 136
disc is an ideal position for a mechanosensor. Indeed, unlike proteins that lie in parallel to 137
the force-generating sarcomeres, such as integrins, Z disc proteins directly experience 138
contractile force. One Hippo-independent function of Bag3 is to mediate tension-induced 139
autophagy, which might contribute to the increased protein breakdown observed during 140
resistance exercise (127). Additionally, Bag3 regulates Yap and Taz activity by binding to 141
Yap and Taz binding partners, such as the Hippo kinase Lats1, Amotl1 and Amotl2 142
(reviewed in (102)). Given that increased Yap activity can promote muscle hypertrophy (46, 143
148), Bag3-Hippo mechanosensing might be one of the several mechanisms regulating 144
muscle growth in response to mechanical signals. The importance of Bag3 for skeletal 145
muscle is further demonstrated by the finding that a loss-of-function of Bag3 causes severe 146
myopathy symptoms in mice and humans (62, 117). Moreover, the phosphorylation of 147
human BAG3 on Thr285 and Ser 289 decreases in response to endurance exercise (61). 148
Also, BAG3 expression decreases after acute high intensity resistance exercise, but 149
increases together with force-bearing cytoskeleton proteins (136). Therefore, the Hippo-150
dependent and -independent functions of Bag3 are of potentially great interest to exercise 151
physiologists. Currently, it is unclear whether Bag3 is the major mediator of mechanical 152
loading-induced hypertrophy or whether it mainly senses the changes in the stiffness of a 153
cell’s niche, for example satellite cells, and accordingly regulates their behaviour (34). 154
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Cross-talk with Akt-Tsc-mTOR signalling 156
The mTOR pathway has first been linked to overload-induced muscle growth by Baar and 157
Esser. They demonstrated that the phosphorylation of the mTOR-related kinase p70 S6k 158
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correlated with increased muscle mass in a rat electrical muscle stimulation model (11). 159
Since then, many studies have confirmed the key role of mTOR signalling for resistance 160
exercise-induced muscle hypertrophy. This includes a study in humans showing that the 161
mTORC1 inhibitor rapamycin prevented the increased muscle protein synthesis triggered by 162
resistance exercise (28). 163
164
Given that both the Hippo and mTOR networks regulate organ size, it is intuitive to assume a 165
cross-talk between the mTOR and Hippo signalling pathways. This is indeed the case. Akt 166
was initially shown to phosphorylate Yap on Ser127 (13) but this finding was not confirmed 167
by subsequent studies. In another study, the Hippo kinase Mst1 (gene symbol Stk4) was 168
shown to bind and inhibit Akt1 (also known as Pkb) (22). Conversely, Akt phosphorylates 169
Mst1 on Thr387 (65) and Thr120 (161), suggesting that Akt1 and Mst1 regulate each other’s 170
activity. Additionally, the Hippo effector Yap de-represses mTOR by inhibiting the expression 171
of the phosphatase Pten via the Pten-targeting miRNA miR-29 (133). Cross-talk also exists 172
between Tsc1 and Tsc2 and the Hippo effector Yap as Tsc1/2-deficient cells have higher 173
Yap levels due to less Yap degradation via the autophagosome system (83). YAP/TAZ also 174
increase the expression of genes that encode the leucine transporter LAT1 (52), which is 175
significant because leucine is a potent stimulator of mTORC1 signalling (10). Collectively, 176
these findings demonstrate that Hippo and mTOR-mediated growth signals are closely 177
coupled by multiple mechanisms. However, a caveat of this research from an exercise 178
physiology standpoint is that most of the above studies have been conducted in cancer 179
models. Therefore, molecular exercise physiologists now need to test whether these 180
mechanisms also function in an exercise context. 181
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Cross-talk with myostatin-Smad signalling 183
TGFβ and BMPs are two classes of small extracellular molecules that bind to activin 184
receptors. Bound activin receptors then either phosphorylate the receptor-regulated 185
Smad2/3 or Smad1/5/8 proteins, respectively. These two classes of receptor-regulated 186
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Smads compete for the common mediator Smad4 to form either transcriptionally active 187
Smad2/3-4 complexes promoting muscle loss or Smad1/3/5-4 complexes that have recently 188
been proposed to promote muscle growth (114). In skeletal muscle, the knockout of 189
myostatin (gene symbol Gdf8, a TGFβ-related ligand) or its “natural” loss-of-function 190
mutation resulted in a doubling of the muscle size in mice and cattle, respectively (48, 69, 191
95, 96). The link between myostatin and muscle mass was confirmed in humans by showing 192
that a toddler with a high muscle mass was homozygous for a knockout mutation in the first 193
intron of the human myostatin-encoding GDF8 gene (116). Furthermore, dogs with a 194
heterozygous loss of Gdf8 show increased racing performance (105), linking myostatin not 195
only to muscle mass but also to actual athletic performance. If the loss of myostatin is 196
combined with the overexpression of a follistatin transgene, then muscle mass quadruples, 197
suggesting that myostatin is not the only muscle mass regulator in the TGFβ-Smad system 198
(79). 199
200
Several studies have shown that Yap and Taz co-regulate not only Teads but also several 201
other transcription factors, including Smads (143). In line with this, the overexpression of 202
Yap in mouse tibialis anterior muscle reduced the activity of a Smad binding element (SBE) 203
reporter by approximately 85% (46). In contrast, the overexpression of Yap in myoblasts, 204
which are activated satellite cells, potently increases the expression of the Smad regulator 205
Bmp4 (67). This is intriguing because both Yap (67) and Bmp4 (109) stimulate satellite cell 206
proliferation while inhibiting differentiation into myotubes. Several mechanisms have been 207
proposed that can explain how Yap or Taz can interact with Smads. These include the 208
binding of Yap to the inhibitory Smad7 (7, 49), the promotion of Smad1 transcriptional action 209
by Yap binding (3), and an effect of Yap and Taz on Smad2/3 localisation (137). For 210
molecular exercise physiologists, the challenge is to determine whether Hippo-Smad cross-211
talk regulates exercise phenomena and especially where it is involved in skeletal muscle 212
mass regulation. 213
214
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Cross-talk with AMPK and glucose signalling 215
In the above sections, we have discussed the mechanisms connecting the Hippo network to 216
resistance exercise and organ growth signals and signalling modules. Below, we will discuss 217
the cross-talk between Hippo signalling and endurance exercise. 218
219
During the transition from rest to exercise ATP turnover can rise potentially more than 200 220
fold (98). To maintain homeostasis during such a large step change in ATP hydrolysis, 221
systems have evolved to sense energy levels and initiate the signalling processes regulating 222
both short- and long-term adaptations of energy metabolism. In this system, glucose, 223
glycogen, AMP and ADP are sensed principally by the heterotrimeric AMPK complex (53, 224
55). Indeed, exercise increases the concentrations of AMP and ADP in contracting skeletal 225
and cardiac muscle and exercise depletes glycogen, especially in muscle (45). Therefore, it 226
comes as no surprise that AMPK is a key mediator of the adaptation to endurance exercise, 227
particularly in skeletal muscle (54). Several recent studies have demonstrated that AMPK is 228
a regulator of YAP, linking a key exercise kinase to Hippo signalling. 229
230
Both glucose starvation (36, 100, 145) and AMPK activators (26, 100, 145) inhibit Yap in 231
different cell types. This suggests that Yap-dependent growth is inhibited when cellular 232
energy levels are low. Further work led to the identification of the molecular mechanisms 233
mediating this effect. These include the phosphorylation of the Yap regulator Amotl1 on 234
Ser293 by AMPK (26) and the direct phosphorylation of YAP on Ser61/94, which is key for 235
the interaction between Yap and Teads (100, 145). In another study, the Dupont group 236
showed that the glycolytic enzyme phosphofructokinase (PFK1) directly binds to and 237
regulates YAP and TAZ (36). Finally, two studies have identified the AMPK-kinase LKB1 238
(gene symbol STK11) as an AMPK-independent YAP regulator (101, 108). Collectively, 239
these studies demonstrate that glucose starvation and energy stress inhibit YAP via both 240
AMPK-dependent and -independent mechanisms in multiple cell types. 241
242
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The fact that energy stress and the key exercise kinase AMPK regulate Yap suggest that 243
Yap should be affected by exercise and diet. This now needs to be demonstrated in an 244
exercise model. Also, because Hippo signalling responds to glucose and regulates the 245
expression of glucose transporters (145), it should be studied whether Hippo signalling 246
mediates the augmented adaptations in response endurance training under low 247
carbohydrate supply (12), or mediates some of the anti-diabetic effects of exercise. 248
249
Cross-talk with hypoxia signalling 250
During evolution, the rise in atmospheric oxygen was followed by the evolution of oxidative 251
phosphorylation by mitochondria, which use oxygen as their main electron acceptor. The 252
emergence of oxygen-related metabolism drove the evolution of oxygen-sensing systems, 253
as oxygen became critical for survival. Oxygen-sensing systems allow cells and organisms 254
to adapt to low oxygen levels (i.e., hypoxia) especially through the transcription factor 255
hypoxia-inducible factor (Hif1). Hypoxic conditions lead to an increase in the expression 256
levels of the Hif1α isoform by blocking its degradation. The hypoxia-induced increase of 257
Hif1α then induces multiple adaptations through gene expression (126). During exercise, 258
hypoxia-induced signalling is also at work. For example, HIF1α levels increase in response 259
to normoxic endurance exercise (5). Moreover, altitude training is often used to stimulate the 260
molecular adaptations to hypoxia, including the EPO-mediated haematopoiesis that 261
increases the athlete’s oxygen transport capacity (118). 262
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Hypoxia and Hippo signalling also interact. For example, hypoxia activates the E3 ligase 264
Siah2, which leads to the degradation of Lats2. This results in a decreased level of Yap 265
phosphorylation, increasing the activity of Yap in the nucleus (88). Additionally, Yap directly 266
interacts with and stabilises Hif1α (88). Hif1α also promotes the expression of Taz and Taz 267
transactivates Hif1α, highlighting a mechanism by which Taz and Hif1α are acting as 268
reciprocal co-activators (153). It is unknown whether hypoxia-Hippo mechanisms function 269
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during normoxic endurance exercise (5) and mediate adaptations to high altitude or low-270
intensity occlusion training. Direct evidence in an exercise or altitude model is required. 271
272
Sensing of catecholamines and other G protein-coupled receptors (GPCRs) ligands 273
by Hippo 274
Catecholamines, such as adrenaline (US: epinephrine) and noradrenaline (US: 275
norepinephrine), mediate the “fight-or-flight” responses. Catecholamine concentrations 276
generally increase with the intensity and duration of exercise and drive the systemic 277
responses to exercise via the α- and β-adrenergic receptors. These receptors, in turn, signal 278
through G-protein coupled receptors (GPCRs) to trigger exercise adaptations, such as 279
increasing the heart rate and muscle contractility. Moreover, β2 agonists such as clenbuterol 280
promote skeletal muscle hypertrophy, suggesting an involvement of this system in the 281
control of skeletal muscle growth (89). In the renin-angiotensin system (RAS), the 282
angiotensin receptors are also coupled to protein G. The RAS was related to exercise when 283
the ACE I/D polymorphism was associated with exercise-related traits, such as strength and 284
endurance (111). Also, angiogensin II contributes to the adaptation to overload-induced 285
skeletal muscle hypertrophy (47) and stretch-induced cardiac hypertrophy (112). In 286
accordance with this, the ACE I/D polymorphism was associated with the left ventricular 287
mass changes occurring in response to endurance training (103). 288
289
Multiple studies have linked GPCRs to Hippo signalling. Adrenaline/epinephrine represses 290
YAP/TAZ through GαS-coupled GPCRs and protein kinase A (PKA) (74, 158). In contrast, 291
angiotensin II and other ligands signal through the Gα12/13 and Gαq/11 GPCRs to activate 292
YAP/TAZ (150, 160). Given that Yap has been shown to mediate skeletal muscle 293
hypertrophy (46, 148) and can promote cardiac hypertrophy (reviewed in (141)), it will be key 294
to test whether GPCR-Hippo signalling is involved in mediating such adaptations. 295
296
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Interleukin-6 and Hippo 297
Interleukin-6 is a myokine (i.e. a circulating signalling molecule) that is produced by 298
contracting muscle but whose functions are incompletely understood (106, 110). Recently, 299
interleukin-6 has been shown to activate Yap through the gp130 co-receptor in the intestine 300
(125). However, it remains unclear whether this mechanism explains some of the effects of 301
exercise-generated interleukin-6. 302
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Hippo & exercise-related phenomena 304
In the text above we have shown that many resistance and endurance exercise-associated 305
signals can cross-talk to the Hippo signal transduction network (see Figure 1). However, 306
much of this evidence was obtained in the context of cancer or non-exercise contexts. In the 307
following section, we will review a small number of studies that provide evidence for a role of 308
Hippo signalling in the adaptation to exercise. In relation to this, some key findings are 309
summarised in Table 1. Additionally, we review emerging evidence that body height is 310
associated with single nucleotide polymorphisms (SNPs) in the vicinity of Hippo genes. 311
312
Table 1 Key experiments where the perturbation of Hippo members affects skeletal and 313
cardiac muscle in a way that is relevant to exercise physiology. 314
Key protein, experiment Effects of intervention versus control
Reference
MST1: STK4 (protein MST1)
knockout versus wildtype mice,
denervation-induced atrophy in vivo
Attenuation of atrophy: skeletal
muscle atrophy after denervation ↓;
expression of atrophy mediators ↓.
(149)
YAP: Injection of rAAV vector to
express the main YAP1 isoform
versus control into mouse tibialis
anterior in vivo
Hypertrophy: Skeletal muscle mass
per body weight ↑; fibre cross
sectional area ↑; protein synthesis ↑
(no evidence for mTOR
involvement).
(148)
YAP: Electroporation of YAP1 Hypertrophy: Fibre cross sectional (46)
14
versus control constructs into mouse
tibialis anterior in vivo
area ↑ (mTORC1 independent);
MyoD reporter ↑; c-Myc reporter ↑,
MurRF1 reporter ↓; Smad reporter ↓.
YAP: Overexpression of YAP1
S127A, wildtype YAP or empty
vector in satellite cells or cultured
muscle fibres in vitro
Satellite cell proliferation ↑;
differentiation ↓.
(67)
TAZ: Injection of TAZ activator
IBS008738 (specificity unclear)
versus vehicle into mouse tibialis
anterior after cardiotoxin-induced
injury or dexamethasone-induced
atrophy in vivo
Regeneration, atrophy prevention:
IBS008738 injections accelerated
skeletal muscle regeneration after
injury and reduced atrophy after
dexamethasone-induced atrophy.
(157)
TEAD1: Muscle creatine kinase
promoter-driven expression of
TEAD1 in mouse muscle fibres and
heart in vivo
Fast-to-slow muscle phenotype shift but cardiomyopathy:
Extensor digitorum longus
shortening velocity ↓; peak power ↓
by ~40%; fast-to-slow shift in myosin
heavy chains; cardiomyopathy and
heart failure.
(130, 132)
YAP: Transduction of neonatal rat
cardiomyocytes with Yap1 or control
adenovirus in vitro
Cardiomyocyte hypertrophy:
Cardiomyocyte size ↑ (Akt-
independent) and survival ↑ (Akt-
dependent).
(25)
YAP: Inducible, Tnnt2-promoter
driven expression of YAP1 S127A in
foetal and post-natal cardiomyocytes
in vivo
Cardiac proliferation:
Cardiomyocyte proliferation ↑;
relative heart weight ↑; regulation of
cell cycle-related genes.
(139)
Salvador: Inducible, Myh6-driven Cardiac proliferation, (58)
15
knock out of Wwtr1 (Salvador), Lats
1 and Lats2 in adult cardiomyocytes
in mice in vivo; apex resection or
myocardial infarction
regeneration: cardiomyocyte
proliferation ↑, regeneration of
injured hearts.
YAP: α myosin heavy chain-driven
expression of Yap1 S112A in the
mouse heart in vivo (homologue of
human S127A mutation); myocardial
infarction
Cardiac proliferation, regeneration: Cardiomyocyte
proliferation ↑; relative heart weight
↑. After myocardial infarction:
cardiac function ↑, cardiomyocyte
proliferation ↑, fibrosis ↓.
(154)
YAP: inducible expression of α
myosin heavy chain-driven
expression of Yap1 S127A in the
adult mouse heart in vivo;
myocardial infarction
Cardiac proliferation, regeneration: Cardiomyocyte
proliferation ↑; relative heart weight
unchanged. After myocardial
infarction: cardiac function ↑,
cardiomyocyte proliferation ↑, scar
size ↓.
(85)
rAAV, recombinant adeno-associated virus; Nkx2.5 and Tnnt2 are promoters used to drive 315
the specific expression of genes in cardiomyocytes. 316
317
Hippo and adaptive changes in skeletal muscle fibre phenotypes 318
Gollnick and Saltin were the first to demonstrate a higher percentage of slow type 1 muscle 319
fibres and a higher oxidative activity in the muscles of endurance athletes when compared to 320
controls and other athletes (44). They also observed a non-significant increase from 32% to 321
36% in the frequency of slow type 1 fibres in response to endurance training (43). 322
Subsequent research has shown that chronic exercise training programmes mainly induce 323
type 2X-to-2A interconversions (151). 324
325
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In the early 2000’s, the Tsika group investigated the role of MCAT elements and Tead1 326
transcription factors in the regulation of muscle fibre type-specific gene expression (71, 131, 327
140). The functional relevance of this work was demonstrated in vivo using a creatine kinase 328
muscle (CKM) promoter to overexpress Tead1 in mouse skeletal muscle fibres, which 329
caused an increased in slow muscle-specific gene expression in vivo (Table 1, (132)). 330
Functionally, CKM-driven Tead1 overexpression reduced the shortening velocity (Vmax) and 331
increased the contraction and relaxation times of extensor digitalis longus muscles (132). 332
This suggests that Hippo signalling affects muscle fibre type-specific gene expression and 333
fibre type percentages. 334
335
Hippo and skeletal muscle hypertrophy 336
Muscle hypertrophy is a key response to resistance exercise. After resistance exercise, 337
protein synthesis and protein breakdown both increase. In the fed state, protein synthesis is 338
higher than breakdown, resulting in protein accretion and hypertrophy (128). However, the 339
effect of resistance exercise on muscle hypertrophy and strength differs greatly among the 340
human population (64). A key mediator of muscle protein synthesis is mTOR signalling, as 341
shown for example by the inhibitory effect of rapamycin on the increase of muscle protein 342
synthesis after resistance exercise in human muscles (30). The key effect of resistance 343
exercise on muscles is mechanical loading, which was discussed in the first part of this 344
review along with the extensive links between mechanosensing and Hippo signalling 345
(reviewed in (50, 87)), including the Z-disc located Bag3 mechanosensor in skeletal muscle 346
(135, 136). 347
348
Several studies support a link between Hippo signalling, resistance exercise and muscle 349
fibre size. In the first study on Hippo signalling in relation to exercise, the Booth group used 350
chronic stretch overload to induce hypertrophy of the anterior latissimus dorsi muscle and 351
found an increased expression of the skeletal α-actin gene. They showed that stretch 352
overload activated a CATTCC (MCAT) motif-containing luciferase reporter, suggesting that 353
17
Tead transcription factor activity was present during mechanical overload of skeletal muscle 354
(19). In a human study, eight men performed 100 unilateral maximal drop jumps followed by 355
submaximal jumping until exhaustion (75). The mRNA of the Hippo pathway marker genes 356
cysteine-rich angiogenic protein 61 (CYR61) and connective tissue growth factor (CTGF) 357
(77, 164) increased 14- and 2.5-fold 30 min after exercise, respectively. Additionally, CYR61 358
protein levels were approximately 2-fold higher at both 30 min and 48 h after the exercise 359
compared with resting control levels. This suggests that some forms of mechanical loading 360
can induce the expression of Hippo marker genes. However, it is unclear whether the 361
increases of CYR61 and CTGF expression are a direct consequence of altered Hippo 362
signalling. 363
364
Two recent studies linked Yap activity directly to muscle fibre hypertrophy. Watt in the 365
Harvey group used an adeno-associated viral vector (rAAV6)-mediated shRNA knock down 366
strategy to reduce Yap levels in mouse limb muscles. They found a decreased muscle fibre 367
size and reduced protein synthesis (148). Additionally, they used the same rAAV6 system to 368
over express the predominant YAP isoform in muscle and found increases in muscle mass, 369
cross sectional area and protein synthesis (Table 1, (148)). Intriguingly, despite the 370
extensive evidence of cross-talk between Hippo and mTOR signalling discussed in the first 371
part of this review, their YAP interventions did not seem to affect mTOR activity. In another 372
study, the Hornberger group reported that YAP expression increases up to approximately 373
4.5 folds in the hypertrophying plantaris muscle days synergist ablation, a model commonly 374
used to induce skeletal muscle hypertrophy (46). Then, they used electroporation to 375
overexpress YAP in the tibialis anterior muscles and analysed the muscles 7 days later. The 376
fibres overexpressing YAP were larger than control fibres, demonstrating that elevated YAP 377
activity could cause hypertrophy (Table 1). Additionally, they found that YAP induced MyoD 378
and Myc reporters, whilst inhibiting a Smad binding element (CAGA)-containing reporter 379
(46). Reductions in myostatin produce a similar effect on a Smad binding element (CAGA) 380
reporter (166), and a myostatin knock out also induces muscle hypertrophy (95). In 381
18
summary, Hippo members can affect fibre type proportions and increased levels of Yap can 382
induce skeletal muscle hypertrophy. Additionally, Hippo marker genes increase after 383
resistance exercise in human skeletal muscle. 384
385
Hippo and satellite cells 386
Satellite cells were discovered by Mauro using electron microscopy (92) and are now well-387
recognized as the resident stem cells of skeletal muscle (115). The key tool allowing to 388
characterise their function in vivo was the Pax7-DTA knockout mice line, which is used to 389
specifically deplete the satellite cell pool in mouse muscles. Studies with these mice showed 390
that satellite cells are essential for the regeneration of skeletal muscle after injury (2, 81, 391
107), suggesting that, in a sports context, satellite cells are needed to regenerate the 392
muscles damaged by eccentric exercises, such as marathon running (59). In contrast, 393
satellite cell-depleted muscles show a normal hypertrophic response to overload in the short 394
term (93). However, satellite cell-depleted muscle cannot maintain the initial hypertrophy 395
after more than 8 weeks (38), suggesting that satellite cells are essential for muscle 396
regeneration after injury and are required to maintain the size of hypertrophied muscles in 397
the long term. 398
399
Hippo members are key mediators of proliferation and differentiation in satellite cells and 400
myoblasts (mononuclear muscle cells). Yap is active in proliferating C2C12 myoblasts, and 401
high Yap activity promotes their proliferation but inhibits myogenic differentiation (147). In 402
satellite cells, Yap protein levels are low in the quiescent state, but increase when satellite 403
cells become activated and develop into MyoD-expressing myoblasts. Again, high Yap 404
activity resulting from the expression of the constitutively active YAP1 S127A mutant 405
promotes proliferation but inhibits differentiation (67). Conversely, knocking down Yap in 406
satellite cell-derived myoblasts reduces proliferation by approximately 40% (67). The 407
overexpression of YAP1 S127A in satellite cell-derived myoblasts also increases the 408
expression of proliferation-associated genes and known satellite cell regulators, such as 409
19
BMP4 (109) and CD34 (4), while reducing the expression of differentiation markers and the 410
myogenic differentiation regulator Mrf4 (67). Collectively, these results indicate that Yap 411
promotes myoblast and satellite cell proliferation but inhibits differentiation into myotubes 412
and muscle fibres. This suggests that Yap might be an important regulator of muscle 413
development (myogenesis) and satellite cell-derived myoblasts proliferation after injury and 414
in response to hypertrophy. The requirement of Yap and other Hippo members, such as Taz, 415
during the satellite cells response to exercise remains to be formally demonstrated. 416
417
Hippo and the Athlete’s heart 418
The maximal oxygen uptake (VO2max) is the key determinant of an individual’s endurance 419
capacity (27) and is also associated with longevity (15). Early physiological studies in 420
humans demonstrated that one of the key predictors of an individual’s VO2max is the blood 421
flow generated by the heart, termed cardiac output (99), which determines the efficiency of 422
oxygen transport to the exercising musculature. The VO2max and cardiac output parameters 423
respond to exercise training and detraining, as demonstrated by Saltin and colleagues (113). 424
They showed that 20 days of bed rest reduces resting heart volume by approximately 10% 425
and exercise cardiac output by 15%, resulting in a significantly reduced VO2max (113). 426
Conversely, 55 days of endurance exercise training following the bed rest increased cardiac 427
output above pre-bed rest levels. This partially explains the restoration of VO2max (142). 428
429
The increase in cardiac output can be attributed to the development of an athlete’s heart in 430
response to endurance training. Indeed, electrocardiographic studies show that athletes 431
have enlarged hearts (9) which was later confirmed by comparative echocardiography on 432
endurance athletes (91). Generally, the main cellular mechanism underlying the athlete’s 433
heart is cardiomyocyte hypertrophy. For example endurance running training for 8 weeks 434
increases cardiomyocyte size by 17-32% in mice (73). Until several years ago, researchers 435
thought that adult cardiomyocytes were unable to proliferate and regenerate the heart. 436
However, this view is now changing (33). By determining the levels of 14C DNA integration 437
20
from nuclear bomb tests, Bergmann et al. estimated that between 0.45 and 1% of human 438
cardiomyocytes renew per annum. Furthermore, they showed that by the age of 50, 40% of 439
the cardiomyocytes had emerged after birth (14). Moreover, swim endurance training for 2 440
weeks increased the expression of proliferation markers in mouse cardiomyocytes (16), 441
suggesting that exercise promotes cardiomyocytes proliferation, at least in mice. There is 442
emerging evidence supporting the existence of a cardiac stem cell population that may 443
engage in some limited regeneration processes (32) in addition to a low rate renewal of pre-444
existing cardiomyocytes (119). Two recent studies found that both cardiac stem cells and 445
cardiomyocytes proliferate in response to endurance exercise in rodents (80, 146). 446
Collectively, these data demonstrate that endurance exercise increases left ventricular 447
volume, thickness and pumping performance and suggest that these effects occur mainly 448
through cardiomyocyte hypertrophy with a limited contribution of cardiac stem cells and 449
cardiomyocytes proliferation. Consequently, this results in the development of the athlete’s 450
heart, which in turn increases the VO2max and aerobic exercise capacity of an individual. 451
452
The heart can respond to increased load in two different ways, depending upon the nature of 453
the load (94): 454
1) Physiological hypertrophy (i.e., athlete’s heart) can occur as a response to endurance 455
exercise or pregnancy (volumetric hypertrophy) or resistance exercise (non-volumetric 456
hypertrophy); 457
2) Pathological hypertrophy can occur after cardiac injury or in individuals with high blood 458
pressure or defective valves. 459
460
Physiological hypertrophy, which is associated with exercise or pregnancy, differs from 461
pathological hypertrophy by the nature of the stimuli, the structural response, the absence of 462
fibrosis and the molecular drivers leading to the adaptation (94). Generally, physiological 463
hypertrophy does not progress into cardiac dysfunction. In contrast, pathological hypertrophy 464
often decompensates, reducing cardiac function and resulting in end-stage heart failure (72). 465
21
Both types of hypertrophy differ at the molecular level in their response the divergent stimuli 466
(1). 467
468
Currently, whether and how Hippo signalling contributes to the different forms of cardiac 469
hypertrophy remains incompletely understood. Several studies show that Yap loss- or gain-470
of-function in the embryonic heart is frequently lethal (reviewed by (84, 141, 155)). This 471
suggests that normal Yap function is essential for normal cardiac development. Presumably, 472
Yap is active only in certain cell populations during specific periods, which could explain why 473
permanent Yap gain- or loss-of-function has such a detrimental effect. There is some 474
evidence that Hippo signalling is perturbed during pathological cardiac hypertrophy. Yap is 475
expressed at higher levels and dephosphorylated (activated) in samples obtained from 476
pathologically hypertrophied human hearts (144). Furthermore, Yap is activated in hearts 477
stressed by pathological pressure overload (144) and in the area bordering a myocardial 478
infarction in mice (25). 479
480
Are Hippo members contributing to the formation of the athlete’s heart in response to 481
exercise? Although this question has not been addressed directly, published data suggest 482
possible roles for Hippo members in mediating the athlete’s heart (see also Table 1). First, 483
Yap1 overexpression in cultured neonatal rat cardiomyocytes promotes hypertrophy and 484
survival compared to control cardiomyocytes (25). In contrast, two other teams reported no 485
cardiomyocyte hypertrophy upon Yap activation in postnatal mouse hearts in vivo (139, 154). 486
The reasons behind these contrasting results are unknown and so it is unclear whether 487
Hippo signalling contributes to cardiomyocyte hypertrophy in response to exercise (73). 488
489
Another response of the heart to endurance exercise is the limited proliferation of 490
cardiomyocytes and cardiac stem cells in rodents (16, 80, 146). While it has not been tested 491
whether Hippo members promote cardiomyocyte or cardiac stem cell proliferation in 492
response to endurance exercise, evidence supporting that Hippo members regulate the 493
22
proliferation of adult cardiomyocytes and can enhance regeneration after cardiac injury has 494
been reported (Table 1). Knocking out the Hippo members Sav1 or Lats1/2 in adult mouse 495
cardiomyocytes increases proliferation, promotes regeneration after myocardial infarction 496
and reduces scar tissue formation (58). Similarly, Yap1 S112A overexpression in 497
cardiomyocytes improves cardiac regeneration after myocardial infarction, both in neonatal 498
and adult mice, with evidence for increased cardiomyocyte proliferation compared to controls 499
(154). Finally, in a mouse model of myocardial infarction, forcing human YAP expression in 500
the heart using adeno-associated virus delivery increases cardiomyocyte proliferation and 501
improves cardiac function as well as survival (85). 502
503
In summary, the normal function of Yap and Hippo signalling is essential for normal cardiac 504
development. Currently, it is unknown whether Hippo members and Yap in cardiomyocytes 505
and cardiac stem cells respond to exercise and contribute to the development of an athlete’s 506
heart. Available studies suggest that Yap can promote cardiomyocyte hypertrophy in some 507
contexts, while, in other contexts, Yap appears to promote cardiomyocyte proliferation and 508
enhance cardiac regeneration after injury. 509
510
Hippo & body height 511
Body height is a key factor in sports, which is most striking in NBA basketball players. Body 512
height is approximately 70-90% inherited (121) and depends on hundreds, if not thousands, 513
of common DNA sequence variations with a small effect size (152). In rare cases, body 514
height can be affected by single, rare mutations with a large effect size. Examples for the 515
latter are dwarfism caused by FGFR3 mutations (37), and acromegaly resulting from AIP 516
gene mutations (20). 517
518
Given that a core function of Hippo signalling is to control cell numbers, one would expect 519
links between Hippo gene DNA sequence variations and body height. Interestingly, genome-520
wide association studies (GWAS) involving the analysis of data from up to 250,000 521
23
individuals (152) show that single nucleotide polymorphisms (SNPs) in several Hippo genes 522
are associated with body height (23, 78, 152). Indeed, SNPs associated with genes 523
encoding for LATS2, TEAD1, YAP1, VGLL2, VGLL3, and VGLL4 are associated with body 524
height (23, 57, 78, 152). In the largest meta-analysis study using data obtained from 253,288 525
individuals of recent European ancestry (152), body height-associated SNPs in LATS2 526
(rs1199734), TEAD1 (rs6485978, rs2099745), VGLL2 (rs1405212) and VGLL4 (rs13078528) 527
were identified. In 2010, Lango Allen et al. identified an association between SNPs in TEAD1 528
(rs7926971) and VGLL2 (rs961764) with body height in 133,653 individuals of recent 529
European ancestry. Also, SNPs in YAP1 (rs11225148) and in VGLL3 (rs7628864) were 530
individually associated with a shorter stature during pubertal growth in a longitudinal meta-531
analysis involving 18,737 European individuals (23). Interestingly, the SNP in VGLL3 was 532
only significantly associated with the trait in females. So far, no sex-related differences were 533
reported for the Hippo pathway functions but this association could suggest that such 534
differences might actually exist in some contexts. Finally, a SNP in VGLL4 (rs6772112) was 535
associated with height in 36,227 East Asian ancestry subjects (57). Another interesting 536
association of the study by Cousminer et al. is the identification of a female-specific SNP in 537
LIN28B associated with late pubertal growth (23). The LIN28/LET-7 pathway, which has 538
recently emerged as a potent regulator of organismal development and cellular metabolism 539
(120), has been functionally linked with the Hippo pathway (21, 104). In summary, common 540
DNA sequence variants in several Hippo genes influence body height but the effect of each 541
variant on height is small, presumably as de novo DNA sequence variants with a large effect 542
size either become fixed or lost relatively quickly (17). 543
544
Summary and future research 545
In this review, we have listed mainly indirect evidence suggesting that Hippo signalling may 546
mediate some of the physiological adaptations to exercise and that SNPs, especially in the 547
Hippo transcriptional regulators, are associated with body height as a measure of whole 548
24
body cell numbers. The task for molecular exercise physiologists is now to directly show that 549
these mechanisms mediate adaptation to exercise in exercise models and that Hippo gene 550
variants are associated with sport and exercise-related traits. We end with three questions: 551
1) Because resistance and endurance exercise trigger different adaptations in skeletal 552
muscle, how can it be explained that the activity of Hippo members is both affected by 553
both resistance and endurance exercise-associated signals? 554
2) Given that Hippo signalling affects amino acid (52) and glucose transporter expression 555
(145), can this be used to develop strategies to alter the responsiveness to nutrients? 556
For example, can we target through Hippo modulation the leucine transporter LAT1 (52) 557
to make muscles and other organs more sensitive to protein intake ? Could such 558
strategy be beneficial for strength athletes or in cases of muscle weakness and wasting, 559
for example, in elderly individuals or cancer patients with sarcopenia? 560
3) Given that the Hippo pathway is involved in regulating the fate of many stem cells (129), 561
can this be exploited to develop interventions aimed at improving the repair of muscle, 562
tendons and cartilage after sports injury or in degenerative muscle diseases? 563
564
25
Acknowledgements 565
We are grateful to Prof Anna Krook (Karolinska Institute), Prof Jörg Höhfeld (University of 566
Bonn) and Dr Carsten G Hansen (University of Edinburgh) for their comments on this review. 567
Work in the Aberdeen Hippo lab is funded by the Medical Research Council (grant number 568
99477), Sarcoma UK and Friends of Anchor. AMT is recipient of a postdoctoral fellowship 569
from the Canadian Institutes of Health Research (CIHR). 570
571
Grants 572
BMG is supported by a Wenner-Gren Foundation Postdoctoral Fellowship, a European 573
Foundation for the Study of Diabetes (EFSD) Albert Renold Travel Fellowship and a Novo 574
Nordisk Foundation Challenge Grant. AMT is recipient of a postdoctoral fellowship from the 575
Canadian Institutes of Health Research (CIHR). Work in the Aberdeen Hippo lab is funded 576
by the Medical Research Council (grant number 99477), Sarcoma UK and Friends of 577
Anchor. 578
579
Disclosure Statement 580
We have no conflicts of interest to disclose. 581
582
26
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